Inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

This Application if a provision of Ser. No. 60/014,793 filed Apr. 3,1996.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase FPTase) have been describedin two general classes. The first are analogs of farnesyl diphosphate(FPP), while the second class of inhibitors is related to the proteinsubstrates (e.g., Ras) for the enzyme. The peptide derived inhibitorsthat have been described are generally cysteine containing moleculesthat are related to the CAAX motif that is the signal for proteinprenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al.,PNAS, 88:732-736 (1991)). Such inhibitors may inhibit proteinprenylation while serving as alternate substrates for thefarnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)). In general, deletion of the thiol from a CAAX derivativehas been shown to dramatically reduce the inhibitory potency of thecompound. However, the thiol group potentially places limitations on thetherapeutic application of FPTase inhibitors with respect topharmacokinetics, pharmacodynamics and toxicity. Therefore, a functionalreplacement for the thiol is desirable.

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels(JP.H7-112930).

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It is, therefore, an object of this invention to develop peptidomimeticcompounds that do not have a thiol moiety, and that will inhibitfarnesyl-protein transferase and thus, the post-translationalfarnesylation of proteins. It is a further object of this invention todevelop chemotherapeutic compositions containing the compounds of thisinvention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises peptidomimetic piperidinone-containingcompounds which inhibit the farnesyl-protein transferase. The instantcompounds lack a thiol moiety and thus offer unique advantages in termsof improved pharmacokinetic behavior in animals, prevention ofthiol-dependent chemical reactions, such as rapid autoxidation anddisulfide formation with endogenous thiols, and reduced systemictoxicity. Further contained in this invention are chemotherapeuticcompositions containing these farnesyl transferase inhibitors andmethods for their production.

The compounds of this invention are illustrated by the formulae A, B andC: ##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR2##wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(O)--,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂N--C(O)--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹OC(O)--NR¹⁰ --;

R² and R³ are independently selected from: H; unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, ##STR3## wherein thesubstituted group is substituted with one or more of: 1) aryl orheterocycle, unsubstituted or substituted with:

a) C₁₋₄ alkyl,

b) (CH₂)_(p) OR⁶,

c) (CH₂)_(p) NR⁶ R⁷,

d) halogen,

e) CN,

f) aryl or heteroaryl,

g) perfluoro-C₁₋₄ alkyl,

h) SR^(6a), S(O)R^(6a), SO₂ R^(6a),

2) C₃₋₆ cycloalkyl,

3) OR⁶,

4) SR^(6a), S(O)R^(6a), or SO₂ R^(6a),

5) --NR⁶ R⁷,

6) ##STR4## 7) ##STR5## 8) ##STR6## 9) ##STR7## 10) ##STR8## 11) --SO₂--NR⁶ R⁷, 12) ##STR9## 13) ##STR10## 14) ##STR11## 15) N₃, 16) F, or

17) perfluoro-C₁₋₄ -alkyl; or

R² and R³ are attached to the same C atom and are combined to form--(CH₂)_(u) -- wherein one of the carbon atoms is optionally replaced bya moiety selected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ and R⁵ are independently selected from H and CH₃ ; and any two of R²,R³, R⁴ and R⁵ are optionally attached to the same carbon atom;

R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl andheteroarylsulfonyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR12## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ; or

R⁶ and R⁷ may be joined in a ring;

R⁷ and R^(7a) may be joined in a ring;

R^(6a) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle andaryl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR13## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R₁₀)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- and S(O)_(m) ;

G¹ and G² are independently oxygen or absent, provided that at least oneof G¹ and G² is oxygen;

G³ is oxygen or H₂ ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m)and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X is a bond, --CH₂ --, --C(═O)--, or --S(═O)_(m) --;

Y is unsubstituted or substituted aryl or unsubstituted or substitutedheterocycle, wherein the substituted aryl or substituted heterocycle issubstituted with one or more of:

1) C₁₋₄ alkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) aryl or heterocycle,

e) HO,

f) --S(O)_(m) R^(6a), or

g) --C(O)NR⁶ R⁷,

2) aryl or heterocycle,

3) halogen,

4) OR⁶,

5) NR⁶ R⁷,

6) CN,

7) NO₂,

8) CF₃ ;

9) --S(O)_(m) R^(6a),

10) --C(O)NR⁶ R⁷, or

11) C₃ -C₆ cycloalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 0 or 1;

t is 0 or 1; and

u is 4 or 5; or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula B: ##STR14##wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ ;

R² and R³ are independently selected from: H; unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, ##STR15## wherein thesubstituted group is substituted with one or more of: 1) aryl orheterocycle, unsubstituted or substituted with:

a) C₁₋₄ alkyl,

b) (CH₂)_(p) OR⁶,

c) (CH₂)_(p) NR⁶ R⁷,

d) halogen,

e) CN,

f) aryl or heteroaryl,

g) perfluoro-C₁₋₄ alkyl,

h) SR^(6a), S(O)R^(6a), SO₂ R^(6a),

2) C₃₋₆ cycloalkyl,

3) OR⁶,

4) SR^(6a), S(O)R^(6a), or SO₂ R^(6a),

5) --NR⁶ R⁷, ##STR16## 11) --SO₂ --NR⁶ R⁷, ##STR17## 15) N₃,

16) F, or

17) perfluoro-C₁₋₄ -alkyl; or

R² and R³ are attached to the same C atom and are combined to form--(CH₂)_(u) -- wherein one of the carbon atoms is optionally replaced bya moiety selected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ is selected from H and CH₃ ; and any two of R², R³ and R⁴ areoptionally attached to the same carbon atom;

R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl andheteroarylsulfonyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR18## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ; or

R⁶ and R⁷ may be joined in a ring;

R⁷ and R^(7a) may be joined in a ring;

R^(6a) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle andaryl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR19## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ OC(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹¹ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- and S(O)_(m) ;

G¹ and G² are independently oxygen or absent provided that at least oneof G¹ and G² is oxygen;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m)and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X is a bond, --CH₂ --, --C(═O)--, or --S(═O)_(m) --;

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl,arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl,wherein the substituted group is substituted with one or more of thefollowing:

a) C₁₋₄ alkyl, unsubstituted or substituted with: C₁₋₄ alkoxy, NR⁶ R⁷,C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl; and

2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstitutedC₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein thesubstituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkyl issubstituted with one or two of the following:

a) C ₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) --NR⁶ C(O)R⁷,

e) HO,

f) --S(O)_(m) R^(6a),

g) halogen, or

h) perfluoroalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 0 or 1;

t is 0 or 1; and

u is 4 or 5; or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula C: ##STR20##wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, and R¹¹OC(O)--NR¹⁰ --;

R² and R³ are independently selected from: H; unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, ##STR21## wherein thesubstituted group is substituted with one or more of: 1) aryl orheterocycle, unsubstituted or substituted with:

a) C₁₋₄ alkyl,

b) (CH₂)_(p) OR⁶,

c) (CH₂)_(p) NR⁶ R⁷,

d) halogen,

e) CN,

f) aryl or heteroaryl,

g) perfluoro-C₁₋₄ alkyl,

h) SR^(6a), S(O)R^(6a), SO₂ R^(6a),

2) C₃₋₆ cycloalkyl,

3) OR⁶,

4) SR^(6a), S(O)R^(6a), or SO₂ R^(6a),

5) --NR⁶ R₇,

6) ##STR22## 7) ##STR23## 8) ##STR24## 9) ##STR25## 10) ##STR26## 11)--SO₂ --NR⁶ R⁷, 12) ##STR27## 13) ##STR28## 14) ##STR29## 15) N₃, 16) F,or

17) perfluoro-C₁₋₄ -alkyl; or

R² and R³ are attached to the same C atom and are combined to form--(CH₂)_(u) -- wherein one of the carbon atoms is optionally replaced bya moiety selected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ is selected from H and CH₃ ; and any two of R², R³ and R⁴ areoptionally attached to the same carbon atom;

R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl andheteroarylsulfonyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR30## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ; or

R⁶ and R⁷ may be joined in a ring;

R⁷ and R^(7a) may be joined in a ring;

R^(6a) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle andaryl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR31## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR₁₀)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --NR¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- and S(O)_(m) ;

G¹ and G² are independently oxygen or absent, provided that if G¹ isoxygen then G² is absent and if s=0, G¹ is oxygen;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m)and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X is a bond, --CH₂ --, --C(═O)--, or --S(═O)_(m) --;

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl,arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl,wherein the substituted group is substituted with one or more of thefollowing:

a) C₁₋₄ alkyl, unsubstituted or substituted with:

C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m)R^(6a), or --C(O)NR⁶ R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl; and

2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstitutedC₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein thesubstituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkyl issubstituted with one or two of the following:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) --NR⁶ C(O)R⁷,

e) HO,

f) --S(O)_(m) R^(6a),

g) halogen, or

h) perfluoroalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 1;

t is 0 or 1; and

u is 4 or 5; or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula B: ##STR32##wherein: R^(1a) is independently selected from: hydrogen and C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,and

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O-- and--N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from H and CH₃ ;

R² is H; ##STR33## or C₁₋₅ alkyl, unbranched or branched, unsubstitutedor substituted with one or more of:

1) aryl,

2) heterocycle,

3) OR⁶,

4) SR^(6a), SO₂ R^(6a), or

5) ##STR34## and any two of R², R³, and R⁴ are optionally attached tothe same carbon atom;

R⁶, R⁷ and R^(7a) are independently selected from:

H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl and heterocycle, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R^(6a) is selected from:

C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)-- and S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ;

G¹ is absent;

G² is oxygen;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl andisoquinolinyl;

X is --CH₂ -- or --C(═O)--;

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl,arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl,wherein the substituted group is substituted with one or more of thefollowing:

a) C₁₋₄ alkyl, unsubstituted or substituted with:

C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m)R^(6a), or --C(O)NR⁶ R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl; and

2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstitutedC₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein thesubstituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkyl issubstituted with one or two of the following:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) --NR⁶ C(O)R⁷,

e) HO,

f) --S(O)_(m) R^(6a),

g) halogen, or

h) perfluoroalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 0 or 1;

t is 0 or 1; and

u is 4 or 5; or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention areillustrated by the formula D: ##STR35## wherein: R^(1a) is selectedfrom: hydrogen and C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ and R⁴ independently selected from H and CH₃ ;

R² is selected from H; ##STR36## and C₁₋₅ alkyl, unbranched or branched,unsubstituted or substituted with one or more of:

1) aryl,

2) heterocycle,

3) OR⁶,

4) SR^(6a), SO₂ R^(6a), or

5) ##STR37## and R², R³ and R⁴ are optionally attached to the samecarbon atom;

R⁶ and R⁷ are independently selected from:

H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl and heterocycle, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R^(6a) is selected from:

C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

R^(9a) is hydrogen or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)-- and S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ;

X is --CH₂ -- or --C(═O)--;

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl,arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl,wherein the substituted group is substituted with one or more of thefollowing:

a) C₁₋₄ alkyl, unsubstituted or substituted with:

C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m)R^(6a), or --C(O)NR⁶ R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl; and

2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstitutedC₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein thesubstituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkyl issubstituted with one or two of the following:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) --NR⁶ C(O)R⁷,

e) HO,

f) --S(O)_(m) R^(6a),

g) halogen, or

h) perfluoroalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;and

r is 0 to 5, provided that r is 0 when V is hydrogen; or thepharmaceutically acceptable salts thereof.

In another preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula E: ##STR38##wherein: R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ and R⁴ independently selected from H and CH₃ ;

R² is selected from H; ##STR39## and C₁₋₅ alkyl, unbranched or branched,unsubstituted or substituted with one or more of:

1) aryl,

2) heterocycle,

3) OR⁶,

4) SR^(6a), SO₂ R^(6a), or

5) ##STR40## and R², R³ and R⁴ are optionally attached to the samecarbon atom;

R⁶ and R⁷ are independently selected from:

H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl and heterocycle, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R^(6a) is selected from:

C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

X is --CH₂ -- or --C(═O)--;

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl,arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl,wherein the substituted group is substituted with one or more of thefollowing:

a) C₁₋₄ alkyl, unsubstituted or substituted with:

C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m)R^(6a), or --C(O)NR⁶ R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl; and

2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstitutedC₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein thesubstituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkyl issubstituted with one or two of the following:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) --NR⁶ C(O)R⁷,

e) HO,

f) --S(O)_(m) R^(6a),

g) halogen, or

h) perfluoroalkyl;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.

In another preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula F: ##STR41##wherein: R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ and R⁴ independently selected from H and CH₃ ;

R² is selected from H; ##STR42## and C₁₋₅ alkyl, unbranched or branched,unsubstituted or substituted with one or more of:

1) aryl,

2) heterocycle,

3) OR⁶,

4) SR^(6a), SO₂ R^(6a), or

5) ##STR43## and R², R³ and R⁴ are optionally attached to the samecarbon atom;

R⁶ and R⁷ are independently selected from:

H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl and heterocycle, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R^(6a) is selected from:

C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

X is --CH₂ -- or --C(═O)--;

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl,arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl,wherein the substituted group is substituted with one or more of thefollowing:

a) C₁₋₄ alkyl, unsubstituted or substituted with:

C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m)R^(6a), or --C(O)NR⁶ R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl; and

2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstitutedC₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein thesubstituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkyl issubstituted with one or two of the following:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) --NR⁶ C(O)R⁷,

e) HO,

f) --S(O)_(m) R^(6a),

g) halogen, or

h) perfluoroalkyl;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.

Examples of the compounds of this invention are as follows:

4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinone

4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenyl-2-piperidinone

4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-1-phenyl-2-piperidinone

(±)cis-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinone

(±)trans-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinone

4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}carbonyl]-1-phenyl-2-piperidinoneand

Ethyl1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylateor a pharmaceutically acceptable salt or optical isomer thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. When any variable (e.g. aryl, heterocycle, R¹, R²etc.) occurs more than one time in any constituent, its definition oneach occurence is independent at every other occurence. Also,combinations of substituents/or variables are permissible only if suchcombinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms; "alkoxy" represents an alkyl group ofindicated number of carbon atoms attached through an oxygen bridge."Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl" is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl oracenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl,pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, andthienyl.

As used herein in the definition of R² and R³, the term "the substitutedgroup" intended to mean a substituted C₁₋₈ alkyl, substituted C₂₋₈alkenyl, substituted C₂₋₈ alkynyl, substituted aryl or substitutedheterocycle from which the substitutent(s) R² and R³ are selected.

As used herein in the definition of R⁶, R^(6a), R⁷ and R^(7a), thesubstituted C₁₋₈ alkyl, substituted C₃₋₆ cycloalkyl, substituted aroyl,substituted aryl, substituted heteroaroyl, substituted arylsulfonyl,substituted heteroarylsulfonyl and substituted heterocycle includemoieties containing from 1 to 3 substitutents in addition to the pointof attachment to the rest of the compound.

As used herein in the definition of R^(1a) and R^(1b), the termsubstituted aryl includes moieties containing from 1 to 3 substitutentsin addition to the point of attachment to the rest of the compound.Preferably, such substitutents are selected from the group whichincludes but is not limited to F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂,NO₂, CN, (C₁ -C₆ alkyl)O--, --OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆alkyl)C(O)NH--, H₂ N--C(NH)--, (C₁ -C₆ alkyl)C(O)--, (C₁ -C₆alkyl)OC(O)--, N₃,(C₁ -C₆ alkyl)OC(O)NH--, phenyl, pyridyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C₁-C₂₀ alkyl.

When R² and R³ are combined to form --(CH₂)_(u) --, cyclic moieties areformed. Examples of such cyclic moieties include, but are not limitedto: ##STR44##

In addition, such cyclic moieties may optionally include aheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to: ##STR45##

Lines drawn into the ring systems from substituents (such as from R²,R³, R⁴ etc.) mean that the indicated bond may be attached to any of thesubstitutable ring carbon atoms. It is understood that the carboncontaining the moiety --C(═O)--Y is substitutable with a secondsubstituent R², R³, R⁴ or R⁵.

When substituents G¹ and/or G² are "absent," the ring carbons to whichG¹ and/or G² are attached are understood to be substituted with twohydrogen atoms and are considered substitutable ring carbon atoms, andare therefore optionally substituted with a substituent selected fromR², R³, R⁴ and R⁵.

Preferably, R^(1a) and R^(1b) are independently selected from: hydrogen,--N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ -- or unsubstituted or substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted phenyl, --N(R¹⁰)₂, R¹⁰)-- and R¹⁰ C(O)NR¹⁰--.

Preferably, R² is selected from: H, ##STR46## and an unsubstituted orsubstituted group, the group selected from C₁₋₈ alkyl, C₂₋₈ alkenyl andC₂₋₈ alkynyl; wherein the substituted group is substituted with one ormore of:

1) aryl or heterocycle, unsubstituted or substituted with:

a) C₁₋₄ alkyl,

b) (CH₂)_(p) OR⁶,

c) (CH₂)_(p) NR⁶ R⁷,

d) halogen,

2) C₃₋₆ cycloalkyl,

3) OR⁶,

4) SR^(6a), S(O)R^(6a), SO₂ R^(6a),

5) --NR⁶ R⁷,

6) ##STR47## 7) ##STR48## 8) ##STR49## 9) ##STR50## 10) ##STR51## 11)--SO₂ --NR⁶ R⁷, 12) ##STR52## 13) ##STR53## 14) ##STR54## 15) N₃, or 16)F.

Preferably, R³ is selected from: hydrogen and C₁ -C₆ alkyl.

Preferably, R⁴ is hydrogen.

Preferably, R⁶, R⁷ and R^(7a) is selected from: hydrogen, unsubstitutedor substituted C₁ -C₆ alkyl, unsubstituted or substituted aryl andunsubstituted or substituted cycloalkyl.

Preferably, R^(6a) is unsubstituted or substituted C₁ -C₆ alkyl,unsubstituted or substituted aryl and unsubstituted or substitutedcycloalkyl.

Preferably, R⁹ is hydrogen or methyl. Most preferably, R^(a) ishydrogen.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, Y is selected from unsubstituted or substituted phenyl,unsubstituted or substituted naphthyl, unsubstituted or substitutedpyridyl, unsubstituted or substituted furanyl and unsubstituted orsubstituted thienyl. More preferably, Y is unsubstituted or substitutedphenyl.

Preferably, Z is selected from unsubstituted or substituted phenyl,unsubstituted or substituted naphthyl, unsubstituted or substitutedpyridyl, unsubstituted or substituted furanyl, unsubstituted orsubstituted thienyl, unsubstituted or substituted C₁ -C₆ alkyl andunsubstituted or substituted C₃ -C₆ cycloalkyl. More preferably, Z isunsubstituted or substituted phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, in compounds of the formula A, G¹ is oxygen and G² isabsent.

Preferably, in compounds of the formula B, G² is oxygen and G¹ isabsent.

Preferably, in compounds of the formula C, G¹ is oxygen and G² isabsent.

Preferably, n and r are independently 0, 1, or 2.

Preferably p is 1, 2 or 3.

Preferably s is 0.

Preferably t is 1.

Preferably, the moiety ##STR55## is selected from: ##STR56##

It is intended that the definition of any substituent or variable (e.g.,R^(1a), R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,--N(R¹⁰)₂ represents --NH₂, --NHCH₃, --NHC₂ H₅, etc. It is understoodthat substituents and substitution patterns on the compounds of theinstant invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art, as well as those methods setforth below, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-14, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R and R^(a), asshown in the Schemes, represent the substituents R², R³, R⁴, and R⁵ ;however their point of attachment to the ring is illustrative only andis not meant to be limiting.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes.

Synopsis of Schemes 1-14:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part. Ageneral synthesis of multiply substituted piperidinones is illustratedin Scheme 1. Thus, a suitably substituted bromoacetonitrile is treatedwith the sodium salt of diethylmalonate to provide the diester I.Intermediate I is itself deprotonated and alkylated to provide thetriester II, which, upon catalytic hydrogenation spontaneously cyclizesto the lactam III. Acidic rearragngement provides the substitutedpiperidone IV.

As shown is Scheme 2, the piperidone nitrogen may be arylated byemploying a triaryl bismuth-copper coupling. The resulting diester Vacan then be converted to the acid VIa and the aldehyde VIIa byprocedures well known in the art. Scheme 3 illustrates the analogouspreparation of the piperidone having an alkyl substitutent on the ringnitrogen.

The aldehyde intermediates VII can undergo a Wittig coupling with aprotected imidazole to provide compound IX, which can then becatalytically reduced to the intermediate X (Scheme 4). Intermediate Xcan be deprotected to provide the instant compound XI or it can befurther alkylated to eventually provide the instant compound XII.

Synthesis of compounds of the invention that have an alternateconnectivity of the piperidinon-4-ylethyl to the preferred imidazolylmoiety is illustrated in Scheme 4a. The Scheme illustrates use of asuitably substituted protected piperidine XIII, which is eithercommercially avaiable or may be prepared by techniques known in the art,as the precursor to the 2-piperidinone XV. The nitrogen of intermediateXV may then be functionalized and the suitably substituted imidazolylmoiety incorporated via nucleophilic displacement.

Schemes 4b and 4c illustrate syntheses of suitably substitutedhomologous 4-hydroxymethyl 2-piperidinones, that may be utilized in thereactions illustrated in Scheme 4a, starting with commercially availablematerials.

Schemes 4d and 4e illustrate alternate syntheses of the homologouspiperidinon-4-ylmethyl-1-imidazolyl compounds starting with thepreviously described intermediate IV.

The key intermediates whose syntheses are illustrated in Schemes 2, 3a,3b and 3c may also be utilized in the subsequent reactions.

Scheme 5 illustrates the preparation of the instant compound wherein thelinker between the piperidone and the heterocyclic substitutent is acarbonyl. Thus the protected imidazolyl Grignard XVI is reacted with thekey intermediate VII to provide the secondary alcohol, which can beoxidized and alkylated as illustrated above to provide the instantcompound XVII. Scheme 6 illustrates the analogous synthesis of theinstant compound XVIII wherein the heterocyclic moity is linked to thepiperidone carbon by an acetyl linker.

The carboxylic acid VI can be converted to the phosphonium salt XIXwhich can then be coupled to a variety of aldehydes, such as XX, asshown in Scheme 7. The aldehydes can be prepared by standard procedures,such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kestenin Organic Syntheses, 1988, 67, 69-75), from the appropriate amino acid.The coupling reaction provides the unsaturated intermediate, which iscatalytically reduced to the bisprotected diamine XXI. The product XXIcan be deprotected to give the instant compound XXII withtrifluoroacetic acid in methylene chloride. The final product XXII isisolated in the salt form, for example, as a trifluoroacetate,hydrochloride or acetate salt, among others. The product diamine XXIIcan further be selectively protected to obtain XXIII, which cansubsequently be reductively alkylated with a second aldehyde to obtainXXIV. Removal of the protecting group, and conversion to cyclizedproducts such as the dihydroimidazole XXV can be accomplished byliterature procedures.

If the phosphonium XIX is coupled with with an aldehyde which also has aprotected hydroxyl group, such as XXVI in Scheme 8, the protectinggroups can be subsequently removed to unmask the hydroxyl group (Schemes8, 9). The alcohol can be oxidized under standard conditions to e.g. analdehyde, which can then be reacted with a variety of organometallicreagents such as Grignard reagents, to obtain secondary alcohols such asXXIX. In addition, the fully deprotected amino alcohol XXX can bereductively alkylated (under conditions described previously) with avariety of aldehydes to obtain secondary amines, such as XXXI (Scheme9), or tertiary amines.

The Boc protected amino alcohol XXVII can also be utilized to synthesize2-aziridinylmethylpiperidones such as XXXII (Scheme 10). Treating XXVIIwith 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such asdimethylformamide led to the formation of aziridine XXXII. The aziridinereacted in the presence of a nucleophile, such as a thiol, in thepresence of base to yield the ring-opened product XXXIII.

In addition, as illustrated in Scheme 11, the phosphonium XVIII can bereacted with aldehydes derived from amino acids such as O-alkylatedtyrosines, according to standard procedures, to obtain compounds such asXXXIII. When R' is an aryl group, catalytic hydrogenation of XXXIII alsounmasks the phenol, and the amine group is then deprotected with acid toproduce XXXV. Alternatively, when R' is not an aryl group, XXXV is anO-alkylated phenolic amines.

Schemes 12-15 illustrate syntheses of suitably substituted aldehydesuseful in the syntheses of the instant compounds wherein the variable Wis present as a pyridyl moiety. Similar synthetic strategies forpreparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art. ##STR57##

The instant compounds are useful as pharmaceutical agents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas activity (i.e., neurofibromin (NF-1), neu, scr, abl, Ick, fyn) or byother mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal,2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 14-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinonehydrochloride ##STR58## Step A: 1-Phenyl-2-piperidinone-4,4-dicarboxylicacid diethyl ester

2-Piperidinone-4,4-dicarboxylic acid diethyl ester, prepared asdescribed in U.S. Pat. No. 4,870,173, is dissolved in methylene chlorideand treated with triphenylbismuth (1.5 equivalents), copper(II)acetate(1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17h at 20° C. in dichloromethane (60 mL). The reaction mixture wasadsorbed onto silica gel and chromatographed to provide the titlecompound.

Step B: 1-Phenyl-2-piperidinone-4-carboxylic acid ethyl ester

The product from Step A (4.78 g, 14.98 mmol) was dissolved in DMSO (90mL) containing water (0.27 mL, 14.98 mmol) and lithium chloride (1.27 g,29.96 mmol). The reaction was heated at 180° C. under argon for 3.5 h.The cooled reaction mixture was partitioned between ethyl acetate andwater. Ther organic phase was washed with saturated brine, and driedover magnesium sulfate. The title compound was isolated as a white solidfollowing chromatography on silica gel with 50% ethyl acetate in hexane.

Step C: 1-Phenyl-2-piperidinone-4-carboxylic acid

The product from Step B (2.60 g, 10.52 mmol) was dissolved in THF (60mL) and lithium hydroxide hydrate (2.15 g, 51 mmol) and water (10 mL)were added. The reaction was stirred for 4 h at room temperature, atwhich time 6N aqueous hydrogen chloride solution was added to adjust thepH to 1, and the product extracted with ethyl acetate. The organic phasewas dried with magnesium sulfate, filtered and evaporated to reveal thetitle compound.

Step D: 4-Hydroxymethyl-1-phenyl-2-piperidinone

The product from Step C (1.57 g, 7.16 mmol) was dissolved in THF (30 mL)and triethylamine (1.20 mL, 8.59 mmol) was added. The reaction wascooled to 0° C. under argon, and ethyl chloroformate added (0.82 mL,8.59 mmol). The reaction was stirred for 1 h at 0° C., and then sodiumborohydride was added (0.81 g, 21.5 mmol). After 3 h, the reaction wasquenched by the addition of saturated sodium bicarbonate solution. Theaqueous phase was extracted with ethyl acetate. The organic phase waswashed with 2% aqueous potassium hydrogen sulfate and saturated brine.After drying over magnesium sulfate, the crude product waschromatographed on silica gel with 5% methanol in chloroform. The titlecompound was obtained as a white solid.

Step E: 1-Trityl-4-(4-cyanobenzyl)-imidazole.

To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reactionstirred under argon at 20° C. The suspension was cooled to 0° C. andα-bromo-p-toluinitrile (9.33 g, 47.6 mmol) in THF (100 mL) was addeddropwise over a period of 10 min. The reaction was then allowed to stirat 20° C. for 6 h and bis(triphenylphosphine)Nickel II chloride (2.4 g,3.64 mmol) and 4-iodotrityl imidazole (15.95 g, 36.6 mmol) were added inone portion. The resulting mixture was stirred 16 h at 20° C. and thenquenched by addition of saturated ammonium chloride solution (100 mL)and the mixture stirred for 2 h. Saturated sodium bicarbonate solutionwas added to give a pH of 8 and the solution was extracted with ethylacetate (2×250 mL), dried with magnesium sulfate, and the solventevaporated in vacuo. The residue was chromatographed on silica gel with0-20% ethyl acetate in methylene chloride to afford the title compoundas a white solid.

¹ H NMRδCDCl₃ (7.54 (2H,d, J=7.9Hz), 7.38(1H,s), 7.36-7.29 (11H,m),7.15-7.09(6H,m), 6.58(1H,s), and 3.93(2H,s)ppm.

Step F: 4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinonehydrochloride

The product from Step D (0.205 g, 1.00 mmol) and the product from Step E(0.425 g, 1.00 mmol) were dissolved in methylene chloride (2 mL)containing diisopropylethylamine (0.191 mL, 1.10 mmol) and cooled to-78° C. under argon. Trifluoromethane sulfonic anhydride was added(0.173 mL, 1.03 mmol) and the reaction stirred at -78° C. for 1 h,followed by warming to room temperature over 2 h. The solvent wasevaporated, and the residue dissolved in methanol. After refluxing for30 min, the methanol was evaporated, and the residue is partitionedbetween ethyl acetate and saturated sodium bicarbonate solution. Theorganic phase is washed with saturated brine, dried over magnesiumsulfate, filtered and concentrated. The free base product waschromatographed on silica gel with 3% methanol in methylene chloridefollwed by 7% 9:1 methanol:ammonium hydroxide in methylene chloride. Thetitle compound was obtained after conversion to the hydrochloride salt.FAB ms: 371 (M+1). Anal. Calc for C₂₃ H₂₂ N₄ O·HCl·H₂ O, C, 65.01; H,5.93; N,13.19. Found: C, 64.77; H, 5.89; N, 13.11.

Example 24-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenylpiperidin-2-onehydrochloride ##STR59## Step A:1-tert-Butoxycarbonyl-4-hydroxyethylpiperidine

4-(2-Hydroxyethyl)piperidine (4.91 g, 38.06 mmol) was dissolved inmethylene chloride (80 mL) and di-tert-butyl dicarbonate (8.71 g, 39.96mmol) was added. After stirring at room temperature overnight, saturatedsodium bicarbonate was added, and the layers separated. The organicphase was washed with 2% potassium hydrogen sulfate, saturated sodiumcarbonate and saturated brine, then dried over magnesium sulfate. Thetitle compound was obtained as a yellow oil.

Step B: 4-(2-Acetoxyethyl)-1-tert-butoxycarbonylpiperidine

The product from Step A (6.62 g, 28.90 mmol) was dissolved in methylenechloride (50 mL) containing pyridine (5.8 mL, 72.27 mmol). The reactionwas cooled to 0° C. under argon, and acetic anhydride added (3.3 mL,34.68 mmol). The reaction was stirred overnight at room temperature.Saturated sodium bicarbonate solution was added, and the layersseparated. The organic phase was washed with 10% aqueous hydrogenchloride, saturated sodium bicarbonate solution, and saturated brine.The organic phase was dried over magnesium sulfate. The title compoundwas obtained as an oil.

Step C: 4-(2-Acetoxyethyl)-1-tert-butoxycarbonylpiperidin-2-one

The product from Step B (0.275 g, 1.01 mmol) was dissolved in ethylacetate (5 mL). A solution of sodium periodate in water (0.5 g in 5 mL)and ruthenium tetroxide (13 mg, 0.10 mmol) was added, and theheterogeneous reaction stirred vigorously overnight at room temperature.An additional portion of sodium periodate in water was added (0.5 g in 5mL) and the reaction stirred overnight. The reaction was quenched with10% sodium thiosulfate, and filtered through celite. The phases wereseparated, and the organic phase dried over magnesium sulfate.Filtration and evaporation gave the title compound.

Step D: 4-(2-Acetoxyethyl)piperidin-2-one

The product from Step C is dissolved in 2:1 methylene chloride andtrifluoroacetic acid. The reaction is stirred for 1 h, and evaporated,giving the title compound.

Step E: 4-(2-Acetoxyethyl)-1-phenylpiperidin-2-one

The product from Step D is dissolved in methylene chloride and treatedwith triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at20° C. in dichloromethane (60 mL). The reaction mixture is adsorbed ontosilica gel and chromatographed to provide the title compound.

Step F: 4-(2-Hydroxyethyl)-1-phenylpiperidin-2-one

The product from Step E is hydrolyzed according to the proceduredescribed in Example 1, Step C, giving the title compound.

Step G:4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenylpiperidin-2-onehydrochloride

The product from Step F (1 eq) and the product from Example 1, Step E (1eq) were dissolved in methylene chloride containingdiisopropylethylamine , cooled to -78° C. under argon and treated withtrifluoromethane sulfonic anhydride as described in Example 1, Step F.After methanolysis, the title compound was isolated by chromatography onsilica gel.

Example 34-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-1-phenyl-2-piperidinonehydrochloride ##STR60## Step A: 1-Phenyl-2-piperidinone-4,4-dicarboxylicacid diethyl ester

2-Piperidinone-4,4-dicarboxylic acid diethyl ester, prepared asdescribed in U.S. Pat. No. 4,870,173, is dissolved in methylene chlorideand treated with triphenylbismuth (1.5 equivalents), copper(II)acetate(1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17h at 20° C. in dichloromethane (60 mL). The reaction mixture is adsorbedonto silica gel and chromatographed to provide the title compound.

Step B: 1-Phenyl-2-piperidinone-4,4-dicarboxylic acid

The product from Step A is dissolved in methanol and 5% aqueous sodiumhydroxide added. When the hydrolysis is complete, 6 N aqueoushydrochloric acid is added to obtain pH 1, and the solution extractedwith ethyl acetate. The organic phase is washed with saturated brine,dried over magnesium sulfate, filtered and concentrated to provide thetitle compound.

Step C: 1-Phenyl-2-piperidinone-4-carboxylic acid

The product from step B is dissolved in toluene and refluxed for 6 h.The reaction is cooled and concentrated to provide the title compound.

Step D: 1-Phenyl-2-piperidinone-4-carboxylic acid methyl ester

The product from Step C is dissolved in 10% methanol in toluene, andtrimethylsilyldiazomethane added. The reaction is quenched with aceticacid and concentrated. The residue is partitioned between ethyl acetateand saturated sodium bicarbonate solution. The organic phase is washedwith saturated brine, dried over magnesium sulfate, filtered andconcentrated to provide the title compound.

Step E: 4-Formyl-1-phenyl-2-piperidinone

The product from Step D is dissolved in THF and cooled to -78° C. undernitrogen. A solution of diisobutylaluminum hydride (1 eq.) in toluene isadded dropwise. After 30 min, the reaction is quenched with saturatedsodium potassium tartrate solution. The mixture is extracted with ethylacetate, and the organic phase washed with saturated brine, and driedover MgSO₄. Filtration and concentration provides the title compound.

Step F: 4-Hydroxymethyl-1-triphenylmethylimidazole

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260mmol) in 250 mL of dry DMF at room temperature is added triethylamine(90.6 mL, 650 mmol). A white solid precipitated from the solution.Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF is addeddropwise. The reaction mixture is stirred for 20 hours, poured over ice,filtered, and washed with ice water. The resulting product is slurriedwith cold dioxane, filtered, and dried in vacuo to provide the titledproduct as a white solid which is sufficiently pure for use in the nextstep.

Step G: 4-Chloromethyl-1-triphenylmethylimidazole

The product from Step F is dissolved in chloroform and cooled to 0° C.under nitrogen. Thionyl chloride (molar equivalent) is added slowly viasyringe. The reaction is stirred for 30 min, and extracted with sodiumbicarbonate solution. The organic phase is dried over magnesium sulfate,filtered and concentrated to provide the title compound.

Step H: 4-Diethylphosphonomethyl-1-triphenylmethylimidazole

The product from Step G is dissolved in acetonitrile and cooled to 0° C.Triethyl phosphite (1 equivalent) and sodium iodide (1 equivalent) wereadded, and the reaction stirred at room temperature overnight. Thereaction is quenched with ammonium chloride, and extracted with ethylacetate. The organic phase is dried over magnesium sulfate, filtered andconcentrated to provide the title compound.

Step I:4-[2-{1-(Triphenylmethyl)-4-imidazolyl}ethenyl]-1-phenyl-2-piperidinone

The product from Step H is dissolved in THF and cooled to -78° C. undernitrogen. A solution of LDA in THF is added dropwise. The reaction isstirred at -78° C. for 1 h, then a solution of4-formyl-1-phenyl-2-piperidinone from Step E is added, and the reactionwarmed to room temperature overnight. The reaction is quenched withammonium chloride solution, and extracted with ethyl acetate. The titlecompound is obtained after chromatography on silica gel

Step J:4-[2-{1-(Triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone

The product from Step I is dissolved in methanol and hydrogenated at 60psi hydrogen with 10% palladium on carbon. When reaction is complete,the catalyst is filtered and the title compound obtained afterevaporation of solvent.

Step K:4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-1-phenyl-2-piperidinonehydrochloride

The product from Step J is dissolved in acetonitrile and reacted with4-cyanobenzylbromide (1 equivalent) at room temperature overnight. Thereaction is concentrated in vacuo, and the residue dissolved inmethanol. The methanol solution is refluxed for 3 h and thenconcentrated. The residue is partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The organic phase is washed withsaturated brine, dried over magnesium sulfate, filtered andconcentrated. The title compound is obtained after purification bysilica gel chromatography, and conversion to the hydrochloride salt.

Example 4 (±)cis- and(±)trans-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinonehydrochloride ##STR61## Step A: (±)cis- and(±)trans-3-Methyl-1-phenyl-4-[2-{1-triphenylmethyl)-4-imidazolyl}ethyl]-2-piperidinone

4-[2-{1-(Triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone inTHF is added to a solution of 1 eq lithium hexamethyldisilylazide in THFat -78° C., under argon. The reaction is stirred for 30 min, and 1 eqmethyl iodide is added. The reaction is warmed to room temperature,quenched with saturated ammonium sulfate solution, and extracted withethyl acetate. The organic phase is washed with saturated brine anddried over magnesium sulfate. The crude products are purified by columumchromatography and provide the title compounds.

Step B: (±)cis- and(±)trans-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinonehydrochloride

The title compound is prepared according to the procedure described inExample 3, Step K, except using the product from Step A in place of4-[2-{1-(triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone.The title compound is obtained after purification by silica gelchromatography, and conversion to the hydrochloride salt.

Example 54-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}carbonyl]-1-phenyl-2-piperidinonehydrochloride ##STR62## Step A: N-Methyl N-methoxy1-phenyl-2-piperidinone-4-carboxamide

1-Phenyl-2-piperidinone-4-carboxylic acid is stirred with 1 eqN,O-dimethylhydroxylamine hydrochloride, 1.1 eq EDC·HCl, 1 eqhydroxybenzotriazole in DMF at pH 7 overnight. The reaction is pouredinto water and extracted with ethyl acetate. The organic phase is driedover magnesium sulfate, filtered and concentrated, and provides thetitle compound.

Step B:1-Phenyl-4-[1-triphenylmethyl-4-imidazolyl}carbonyl]-2-piperidinonehydrochloride

1 -Triphenylmethylimidazole-4-magnesium iodide in methylene chloride isprepared as described by R. M. Turner, S. D. Lindell and S. V. Ley in J.Org. Chem., 1991, 56, 5739-5740, and is added to 1 eq of N-methylN-methoxy 1-phenyl-2-piperidinone-4-carboxamide in dichloromethane underargon at -78° C. The reaction is warmed to room temperature and quenchedwith saturated ammonium chloride solution. The reaction is extractedwith ethyl acetate and the organic phase dried over magnesium sulfate,filtered and concentrated, providing the title compound.

Step C:4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}carbonyl]-1-phenyl-2-piperidinonehydrochloride

The title compound is prepared according to the procedure described inExample 3, Step K, except using the product from Step B in place of4-[2-{1-(triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone.The title compound is obtained after purification by silica gelchromatography, and conversion to the hydrochloride salt.

Example 6 Preparation of Ethyl1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate trifluoroacetate salt ##STR63##Step A: Preparation of EthylN-tert-butoxycarbonyl-3-oxo-piperidine-4-carboxylate

A mixture of ethyl N-benzyl-3-oxo-piperidine-4-carboxylate hydrochloridesalt (3.5 g, 11.7 mmol; purified) and 10% palladium on charcoal (0.35 g)in a mixture of ethanol (100 mL) and water (100 mL) was hydrogenated atroom temp. at 60 psi overnight. The resultant mixture was filteredthrough a plug of Celite, and the filtrate was concentrated undervacuum. The residue was dissolved in mixture of triethylamine (5 mL),dioxane (20 mL) and water (19 mL), and treated with di-tert-butyldicarbonate (3.2 g). The reaction mixture was stirred at room temp.overnight. The product mixture was concentrated and the residue waspartitioned between ethyl acetate and aqueous sodium bicarbonate. Theorganic extract was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluting with 20% ethylacetate in hexane. Collection and concentration of appropriate fractionsprovided the title compound as clear colorless oil, which was storedunder argon at -10° C.

Step B: Preparation of EthylN-tert-butoxycarbonyl-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate

To a cold (0° C.) slurry of sodium hydride (0.29 g, 12 mmol) inanhydrous dimethylformamide (50 mL), a solution of ethylN-tert-butoxycarbonyl-3-oxo-piperidine-4-carboxylate (2.73 g, 10 mmol)in DMF (10 mL) was added. The mixture was stirred at 0° C. for 30 min.,and at room temp. for 30 min. The resultant solution was cooled back to0° C. and treated with 3-methylbenzyl bromide (1.63 mL, 12 mmol). Thereaction mixture was stirred at room temp. overnight and concentratedunder vacuum. The residue was partitioned between ethyl acetate andaqueous sodium bicarbonate. The organic extract was washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with 17.5% ethyl acetate in hexane. Collection and concentrationof appropriate fractions provided the title compound.

Step C: Preparation of Ethyl3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt

To a cold (0° C.) solution of ethylN-tert-butoxycarbonyl-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate(1.55 g, 4.13 mmol) in ethyl acetate (75 mL), a stream of anhydroushydrogen chloride gas was bubbled for 20 min. The resultant mixture wasstirred at 0° C. for 1 h, purged with argon for 10 min., andconcentrated under vacuum to provide the title compound as white solid.

Step D: Preparation of Ethyl1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylatetrifluoroacetate salt

A solution of ethyl 3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylatehydrochloride salt (4.13 mmol),1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (1.11 g,4.13 mmol), and diisopropylethylamine (1.58 mL, 9.1 mmol) in anhydrousacetonitrile (10 mL) was heated under reflux overnight. The resultantmixture was concentrated under vacuum, and the residue was partitionedbetween saturated aqueous sodium bicarbonate and ethyl acetate. Theorganic extract was washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluting with a 1:1mixture of chloroform and chloroform saturated with ammonia gas. Aftercollection and concentration of appropriate fractions, the residuefurther purified by subjecting to high pressure liquid columnchromatography on C-18 reverse phase stationary phase. Collection andlyophilization of appropriate fractions provided the title compound aswhite solid. Anal. Calcd for C₂₈ H₃₀ N₄ O₃ ·1.6 TFA·0.1 H₂ O: C, 57.23;H, 4.90; N, 8.56. Found: C, 57.21; H, 4.85; N, 8.53.

Example 7

In vitro inhibition of ras farnesyl transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM [³ H]-farnesyl diphosphate ([³ H]-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0 M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvestor, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the [³ H]-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention described in the above Examplesare tested for inhibitory activity against human FPTase by the assaydescribed above. The compound of the instant invention described inExamples 1 and 6 were tested for inhibitory activity against humanFPTase by the assay described above and were found to have IC₅₀ of ≦10μM.

Example 8

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemeted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi[³⁵ S]methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 9

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR64## wherein: R^(1a) and R^(1b) areindependently selected from:a) hydrogen, b) aryl, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(O)--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) unsubstituted or substituted C₁-C₆ alkyl wherein the substitutent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(O)--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,and R¹¹ OC(O)--NR¹⁰ --;R² and R³ are independently selected from: H;unsubstituted or substituted C₁ -C₈ alkyl, unsubstituted or substitutedC₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl, unsubstitutedor substituted aryl, unsubstituted or substituted ##STR65## wherein thesubstituted group is substituted with one or more of: 1) aryl orunsubstituted or substituted with: a) C₁₋₄ alkyl, b) (CH₂)_(p) OR⁶, c)(CH₂)_(p) NR⁶ R⁷, d) halogen, e) CN, f) aryl, g) perfluoro-C₁₋₄ alkyl,h) SR^(6a), S(O)R^(6a), SO₂ R^(6a), 2) C₃₋₆ cycloalkyl, 3) OR⁶, 4)SR^(6a), S(O)R^(6a), or SO₂ R^(6a), 5) --N R⁶ R⁷, 6) ##STR66## 7)##STR67## 8) ##STR68## 9) ##STR69## 10) ##STR70## 11) --SO₂ --NR⁶ R⁷,12) ##STR71## 13) ##STR72## 14) ##STR73## 15) N₃, 16) F, or 17)perfluoro-C₁₋₄ -alkyl; orR² and R³ are attached to the same C atom andare combined to form --(CH₂)_(u) --; R⁴ and R⁵ are independentlyselected from H and CH₃ ; and any two of R², R³, R⁴ and R⁵ areoptionally attached to the same carbon atom; R⁶, R⁷ and R^(7a) areindependently selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl,aroyl, and arylsulfonyl, unsubstituted or substituted with: a) C₁₋₄alkoxy, b) aryl, c) halogen, d) HO, e) ##STR74## f) --SO₂ R¹¹, or g)N(R¹⁰)₂ ; orR^(6a) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl andaryl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) aryl, c)halogen, d) HO, e) ##STR75## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ;R⁸ isindependently selected from: a) hydrogen, b) aryl, C_(3-C) ₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NH--, andc) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;R⁹ isselected from: a) hydrogen, b) C_(2-C) ₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;R¹⁰ is independently selected from hydrogen, C_(1-C) ₆alkyl, benzyl and aryl; R¹¹ is independently selected from C_(1-C) ₆alkyl and aryl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O,--N(R¹⁰)--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- and S(O)_(m) ; G¹ and G²are independently oxygen or absent, provided that at least one of G¹ andG² is oxygen; G³ is oxygen or H₂ ; V is selected from: a) hydrogen, b)aryl, c) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a heteroatom selected from O, S, and N, and d) C₂ -C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;W is imidazolyl or pyridyl;X is a bond, --CH₂ --, --C(═O)--, or --S(═O)_(m) --; Y is unsubstitutedor substituted aryl, wherein the substituted aryl is substituted withone or more of: 1) C₁₋₄ alkyl, unsubstituted or substituted with:a) C₁₋₄alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) aryl, e) HO, f) --S(O)_(m)R^(6a), or g) --C(O)NR⁶ R⁷, 2) aryl, 3) halogen, 4) OR⁶, 5) NR⁶ R⁷, 6)CN, 7) NO₂, 8) CF₃ ; 9) --S(O)_(m) R^(6a), 10) --C(O)NR⁶ R⁷, or 11) C₃-C₆ cycloalkyl;m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; sis 0; t is 0 or 1; and u is 4 or 5; or an optical isomer orpharmaceutically acceptable salt thereof.
 2. A compound which inhibitsfarnesyl-protein transferase of the formula B: ##STR76## wherein: R^(1a)and R^(1b) are independently selected from:a) hydrogen, b) aryl, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰)--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --, and c) unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substitutent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;R² and R³ are independently selectedfrom: H; unsubstituted or substituted C₁ -C₈ alkyl, unsubstituted orsubstituted C₂ -₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted aryl, unsubstituted or substituted##STR77## wherein the substituted group is substituted with one or moreof: 1) aryl, unsubstituted or substituted with: a) C₁₋₄ alkyl, b)(CH₂)_(p) OR⁶, c) (CH₂)_(p) NR⁶ R⁷, d) halogen, e) CN, f) aryl, g)perfluoro-C₁₋₄ alkyl, h) SR^(6a), S(O)R^(6a), S(O)R^(6a), 2) C₃₋₆cycloalkyl, 3) OR⁶, 4) SR^(6a), S(O)R^(6a), or SO₂ R^(6a), 5) --NR⁶ R⁷,6) ##STR78## 7) ##STR79## 8) ##STR80## 9) ##STR81## 10) ##STR82##11)--SO₂ --NR⁶ R⁷, 12) ##STR83## 13) ##STR84## 14) ##STR85## 15) N₃, 16)F, or 17) perfluoro-C₁₋₄ -alkyl; orR² and R³ are attached to the same Catom and are combined to form --(CH₂)_(u) --; R⁴ is selected from H andCH₃ ; and any two of R², R³ and R⁴ are optionally attached to the samecarbon atom; R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄alkyl, C₃₋₆ cycloalkyl, aryl, aroyl and arylsulfonyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) aryl, c) halogen, d) HO, e)##STR86## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ; orR^(6a) is selected from: C₁₋₄alkyl, C₃₋₆ cycloalkyl and aryl, unsubstituted or substituted with: a)C₁₋₄ alkoxy, b) aryl, c) halogen, d) HO, e) ##STR87## f) --SO₂ R¹¹, org) N(R¹⁰)₂ ;R⁸ is independently selected from: a) hydrogen, b) aryl, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ O C(O)NH--;R⁹ isselected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F,Cl, Br, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;R¹⁰is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl;R¹¹ is independently selected from C₁ -C₆ alkyl and aryl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.--C--, --C(O)--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ -- and S(O)_(m) ; G¹ and G² are independently oxygen orabsent provided that at least one of G¹ and G2 is oxygen; V is selectedfrom: a) hydrogen, b) aryl, c) C₁ -C₂₀ alkyl wherein from 0 to 4 carbonatoms are replaced with a heteroatom selected from O, S, and N, and d)C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m) and Vis not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ;W isimidazolyl or pyridyl; X is a bond, --CH₂ --, --C(═O)--, or --S(═O)_(m)--; Z is selected from: 1) a unsubstituted or substituted group selectedfrom aryl, arylmethyl, and arylsulfonyl, wherein the substituted groupis substituted with one or more of the following:a) C₁₋₄ alkyl,unsubstituted or substituted with:C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl,aryl, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶ R⁷, b) aryl, c) halogen, d)OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂, h) CF₃ ; i) --S(O)_(m) R^(6a), j)--C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl; and 2) unsubstituted C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, unsubstituted C₃ -C₆ cycloalkyl orsubstituted C₃ -C₆ cycloalkyl, wherein the substituted C₁ -C₆ alkyl andsubstituted C₃ -C₆ cycloalkyl is substituted with one or two of thefollowing:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) --NR⁶C(O)R⁷, e) HO, f) --S(O)_(m) R^(6a), g) halogen, or h) perfluoroalkyl;mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; ris 0 to 5, provided that r is 0 when V is hydrogen; s is 0; t is 0 or 1;and u is 4 or 5; or a pharmaceutically acceptable salt thereof.
 3. Acompound which inhibits farnesyl-protein transferase of the formula C:##STR88## wherein: R^(1a) and R^(1b) are independently selected from:a)hydrogen, b) aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) unsubstituted or substituted C₁ -C₆ alkyl whereinthe substitutent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,C₂ -C₆ alkynyl, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂,and R¹¹ OC(O)--NR¹⁰ --;R² and R³ are independently selected from: H;unsubstituted or substituted C₁ -C₈ alkyl, unsubstituted or substitutedC₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl, unsubstitutedor substituted aryl, unsubstituted or substituted ##STR89## wherein thesubstituted group is substituted with one or more of: 1) aryl,unsubstituted or substituted with: a) C₁₋₄ alkyl, b) (CH₂)_(p) OR⁶, c)(CH₂)_(p) NR⁶ R⁷, d) halogen, e) CN, f) aryl, g) perfluoro-C₁₋₄ alkyl,h) SR^(6a), S(O)R^(6a), SO₂ R^(6a), 2) C₃₋₆ cycloalkyl, 3) OR⁶, 4)SR^(6a), S(O)R^(6a), or SO₂ R^(6a), 5) --NR⁶ R⁷, 6) ##STR90## 7)##STR91## 8) ##STR92## 9) ##STR93## 10) ##STR94## 11) --SO₂ --NR⁶ R⁷,12) ##STR95## 13) ##STR96## 14) ##STR97## 15) N₃, 16) F, or 17)perfluoro-C₁₋₄ -alkyl; orR² and R³ are attached to the same C atom andare combined to form --(CH₂)_(u) --; R⁴ is selected from H and CH₃ ; andany two of R², R³ and R⁴ are optionally attached to the same carbonatom; R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl,C₃₋₆ cycloalkyl, aryl, aroyl and arylsulfonyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) aryl, c) halogen, d) HO, e)##STR98## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ; orR^(6a) is selected from: C₁₋₄alkyl, C₃₋₆ cycloalkyl and aryl, unsubstituted or substituted with: a)C₁₋₄ alkoxy, b) aryl, c) halogen, d) HO, e) ##STR99## f) --SO₂ R¹¹, org) N(R¹⁰)₂ ;R⁸ is independently selected from: a) hydrogen, b) aryl, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;R⁹ isselected from: a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR10--;R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl and aryl; R₁₁ is independently selected from C₁ -C₆ alkyland aryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.--C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- and S(O)_(m) ; G¹ and G² areindependently oxygen or absent, provided that if G¹ is oxygen then G² isabsent and if s=0, G¹ is oxygen; V is selected from: a) hydrogen, b)aryl, c) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a heteroatom selected from O, S, and N, and d) C₂ -C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;W is imidazolyl or pyridyl;X is a bond, --CH₂ --, --C(═O)--, or --S(═O)_(m) --; Z is selectedfrom: 1) a unsubstituted or substituted group selected from aryl,arylmethyl, and arylsulfonyl, wherein the substituted group issubstituted with one or more of the following:a) C₁₋₄ alkyl,unsubstituted or substituted with:C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl,aryl, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶ R⁷, b) aryl, c) halogen, d)OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂, h) CF₃ ; i) --S(O)_(m) R^(6a), j)--C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl; and 2) unsubstituted C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, unsubstituted C₃ -C₆ cycloalkyl orsubstituted C₃ -C₆ cycloalkyl, wherein the substituted C₁ -C₆ alkyl andsubstituted C₃ -C₆ cycloalkyl is substituted with one or two of thefollowing:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) --NR⁶C(O)R⁷, e) HO, f) --S(O)_(m) R^(6a), g) halogen, or h) perfluoroalkyl;mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; ris 0 to 5, provided that r is 0 when V is hydrogen; s is 0; t is 0 or 1;and u is 4 or 5; or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 2 of the formula B: ##STR100## wherein:R^(1a) is independently selected from: hydrogen and C₁ -C₆ alkyl;R^(1b)is independently selected from: a) hydrogen, b) aryl, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl, and c) unsubstituted or substituted C₁-C₆ alkyl wherein the substitutent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, cycloalkyl, alkenyl,R¹⁰ O -- and --N(R¹⁰)₂ ;R³ and R⁴ are independently selected from H andCH₃ ; R² is H; ##STR101## or C₁₋₅ alkyl, unbranched or branched,unsubstituted or substituted with one or more of: 1) aryl, 2) OR⁶, 3)SR^(6a), SO₂ R^(6a), or 4) ##STR102## and any two of R², R³, and R⁴ areoptionally attached to the same carbon atom;R⁶, R⁷ and R^(7a) areindependently selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and aryl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) halogen, or c)aryl;R⁶ a is selected from: C₁₋₄ alkyl and C₃₋₆ cycloalkyl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) halogen, or c)aryl;R⁸ is independently selected from: a) hydrogen, b) C₁ -C₆ alkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, Cl-C₆ perfluoroalkyl, F, Cl, R¹⁰ O --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl,R¹⁰ O --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --;R⁹ is selected from: a) hydrogen, b) C₂ -C₆ alkenyl,C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O --, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted by C₁-C₆ perfluoroalkyl, F, Cl, R¹⁰ O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;R¹⁰is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl;R¹¹ is independently selected from C₁ -C₆ alkyl and aryl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, O, --N(R¹⁰)-- and S(O)_(m) ; V is selected from: a)hydrogen, b) aryl, c) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms arereplaced with a heteroatom selected from O, S, and N, and d) C₂ -C₂₀alkenyl, and provided that V is not hydrogen if A¹ is S(O)_(m) and V isnot hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ;G¹ is absent;G² is oxygen; W is imidazolyl or pyridyl; X is --CH₂ -- or --C(═O)--; Zis selected from: 1) a unsubstituted or substituted group selected fromaryl, arylmethyl, and arylsulfonyl, wherein the substituted group issubstituted with one or more of the following:a) C₁₋₄ alkyl,unsubstituted or substituted with:C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl,aryl, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶ R⁷, b) aryl, c) halogen, d)OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂, h) CF₃ ; i) --S(O)_(m) R^(6a), j)--C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl; and 2) unsubstituted C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, unsubstituted C₃ -C₆ cycloalkyl orsubstituted C₃ -C₆ cycloalkyl, wherein the substituted C₁ -C₆ alkyl andsubstituted C₃ -C₆ cycloalkyl is substituted with one or two of thefollowing:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) --NR⁶C(O)R⁷, e) HO, f) --S(O)_(m) R^(6a), g) halogen, or h) perfluoroalkyl;mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5,provided that r is 0 when V is hydrogen; s is 0; t is 0 or 1; and u is 4or 5; or a pharmaceutically acceptable salt thereof.
 5. The compoundaccording to claim 2 of the formula D: ##STR103## wherein: R^(1a) isselected from: hydrogen and C₁ -C₆ alkyl;R^(1b) is independentlyselected from: a) hydrogen, b) aryl, cycloalkyl, R¹⁰ O --, --N(R¹⁰)₂ orC₂ --C₆ alkenyl, and c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R³ and R⁴independently selected from H and CH₃ ; R² is selected from H;##STR104## and C₁₋₅ alkyl, unbranched or branched, unsubstituted orsubstituted with one or more of: 1) aryl, 2) OR⁶, 3) SR^(6a), SO₂R^(6a), or 5) ##STR105## and R², R³ and R⁴ are optionally attached tothe same carbon atom;R⁶ and R⁷ are independently selected from: H; C₁₋₄alkyl, C₃₋₆ cycloalkyl, and aryl, unsubstituted or substituted with:a)C₁₋₄ alkoxy, b) halogen, or c) aryl;R^(6a) is selected from: C₁₋₄ alkyland C₃₋₆ cycloalkyl, unsubstituted or substituted with:a) C₁₋₄ alkoxy,b) halogen, or c) aryl;R⁸ is independently selected from: a) hydrogen,b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R₁₁ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substitutedby C₁ -C₆ perfluoroalkyl, R¹⁰ O --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;R^(9a) ishydrogen or methyl; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyland aryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)-- and S(O)_(m) ; V isselected from: a) hydrogen, b) aryl, c) C₁ -C₂₀ alkyl wherein from 0 to4 carbon atoms are replaced with a heteroatom selected from O, S, and N,and d) C₂ -C₂₀ alkenyl, and provided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ;X is --CH₂ -- or --C(═O)--; Z is selected from: 1) aunsubstituted or substituted group selected from aryl, arylmethyl, andarylsulfonyl, wherein the substituted group is substituted with one ormore of the following:a) C₁₋₄ alkyl, unsubstituted or substitutedwith:C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, HO, --S(O)_(m) R^(6a),or --C(O)NR⁶ R⁷, b) aryl, c) halogen, d) OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂,h) CF₃ ; i) --S(O)_(m) R^(6a), j) --C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl;and 2) unsubstituted C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl,unsubstituted C₃ -C₆ cycloalkyl or substituted C₃ -C₆ cycloalkyl,wherein the substituted C₁ -C₆ alkyl and substituted C₃ -C₆ cycloalkylis substituted with one or two of the following:a) C₁ -₄ alkoxy, b) NR⁶R⁷, c) C₃ -₆ cycloalkyl, d) --NR⁶ C(O)R⁷, e) HO, f) --S(O)_(m) R^(6a),g) halogen, or h) perfluoroalkyl;m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; pis 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V ishydrogen; or a pharmaceutically acceptable salt thereof.
 6. The compoundaccording to claim 2 of the formula E: ##STR106## wherein: R^(1b) isindependently selected from:a) hydrogen, b) aryl, cycloalkyl, R¹⁰ O --,--N(R¹⁰)₂ or C₂ -C₆ alkenyl, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, cycloalkyl, alkenyl, R¹⁰ O --, or --N(R¹⁰)₂ ;R³ andR⁴ independently selected from H and CH₃ ; R² is selected from H;##STR107## and C₁₋₅ alkyl, unbranched or branched, unsubstituted orsubstituted with one or more of: 1) aryl, 2) OR⁶, 3) SR_(6a), SO₂R^(6a), or 4) ##STR108## and R², R³ and R⁴ are optionally attached tothe same carbon atom;R⁶ and R⁷ are independently selected from: H; C₁₋₄alkyl, C₃₋₆ cycloalkyl, and aryl, unsubstituted or substituted with:a)C₁₋₄ alkoxy, b) halogen, or c) aryl;R^(6a) is selected from: C₁₋₄ alkyland C₃₋₆ cycloalkyl, unsubstituted or substituted with:a) C₁₋₄ alkoxy,b) halogen, or c) aryl;R⁸ is independently selected from: a) hydrogen,b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹⁰ C(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substitutedby C₁ -C₆ perfluoroalkyl, R¹⁰ ₀ --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; X is --CH₂ -- or--C(═O)--; Z is selected from: 1) a unsubstituted or substituted groupselected from aryl, arylmethyl, and arylsulfonyl, wherein thesubstituted group is substituted with one or more of the following:a)C₁₋₄ alkyl, unsubstituted or substituted with:C₁ -₄ alkoxy, NR⁶ R⁷, C₃₋₆cycloalkyl, aryl, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶ R⁷, b) aryl, c)halogen, d) OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂, h) CF₃ ; i) --S(O)_(m)R^(6a), j) --C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl; and 2) unsubstitutedC₁ -C₆ alkyl, substituted Cl-C₆ alkyl, unsubstituted C₃ -C₆ cycloalkylor substituted C₃ -C₆ cycloalkyl, wherein the substituted C₁ -C₆ alkyland substituted C₃ -C₆ cycloalkyl is substituted with one or two of thefollowing:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) --NR⁶C(O)R⁷, e) HO, f) --S(O)_(m) R^(6a), g) halogen, or h) perfluoroalkyl;mis 0, 1 or 2; and p is 0, 1, 2, 3 or 4; or a pharmaceutically acceptablesalt thereof.
 7. The compound according to claim 2 of the formula F:##STR109## wherein: R^(1b) is independently selected from:a) hydrogen,b) aryl, cycloalkyl, R¹⁰ O --, --N(R¹⁰)₂ or C₂ -C₆ alkenyl, and c) C₁-C₆ alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R¹⁰O --, or --N(R¹⁰)₂ ;R³ and R⁴ independently selected from H and CH₃ ; R²is selected from H; ##STR110## and C₁₋₅ alkyl, unbranched or branched,unsubstituted or substituted with one or more of: 1) aryl, 2) OR⁶, 3)SR^(6a), SO₂ R^(6a), or 4) ##STR111## and R², R³ and R⁴ are optionallyattached to the same carbon atom;R⁶ and R⁷ are independently selectedfrom: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and aryl, unsubstituted orsubstituted with:a) C₁₋₄ alkoxy, b) halogen, or c) aryl;R^(6a) isselected from: C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted orsubstituted with:a) C₁₋₄ alkoxy, b) halogen, or c) aryl;R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; X is --CH₂ -- or--C(═O)--; Z is selected from: 1) a unsubstituted or substituted groupselected from aryl, arylmethyl, and arylsulfonyl, wherein thesubstituted group is substituted with one or more of the following:a)C₁₋₄ alkyl, unsubstituted or substituted with:C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆cycloalkyl, aryl, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶ R⁷, b) aryl, c)halogen, d) OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂, h) CF₃ ; i) --S(O)_(m)R^(6a), j) --C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl; and 2) unsubstitutedC₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, unsubstituted C₃ -C₆ cycloalkylor substituted C₃ -C₆ cycloalkyl, wherein the substituted C₁ -C₆ alkyland substituted C₃ -C₆ cycloalkyl is substituted with one or two of thefollowing:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) --NR⁶C(O)R⁷, e) HO, f) --S(O)_(m) R^(6a), g) halogen, or h) perfluoroalkyl;mis 0, 1 or 2; and p is 0, 1, 2, 3 or 4; or pharmaceutically acceptablesalt thereof.
 8. A compound which inhibits farnesyl-protein transferasewhichis:4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinone4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenyl-2-piperidinone4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-1-phenyl-2-piperidinone(±)cis-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinone(±)trans-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinone4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}carbonyl]-1-phenyl-2-piperidinoneor Ethyl1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylateor a pharmaceutically acceptable salt or optical isomer thereof.
 9. Thecompound according to claim 8 whichis:4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinone##STR112## or a pharmaceutically acceptable salt or optical isomerthereof.
 10. The compound according to claim 8 whichis:4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenyl-2-piperidinone##STR113## or a pharmaceutically acceptable salt or optical isomerthereof.
 11. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 1. 12. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 2. 13. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 3. 14. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 8. 15. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 11. 16. A method forinhibiting farnesyl-protein transferase which comprises administering toa mammal in need thereof a therapeutically effective amount of acomposition of claim
 12. 17. A method for inhibiting farnesyl-proteintransferase which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 13. 18. Amethod for inhibiting farnesyl-protein transferase which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 14. 19. A pharmaceutical compositionmade by combining the compound of claim 2 and a pharmaceuticallyacceptable carrier.
 20. A process for making a pharmaceuticalcomposition comprising combining a compound of claim 2 and apharmaceutically acceptable carrier.